Abstract:

Mesenchymal stem cells (MSCs) have been isolated from a variety of tissues, such as bone
marrow, skeletal muscle, dental pulp, bone, umbilical cord and adipose tissue. MSCs are used in regenerative
medicine mainly based on their capacity to differentiate into specific cell types and also as bioreactors of
soluble factors that will promote tissue regeneration from the damaged tissue cellular progenitors.

In addition to these regenerative properties, MSCs hold an immunoregulatory capacity, and elicit
immunosuppressive effects in a number of situations. Not only are they immunoprivileged cells, due to the low
expression of class II Major Histocompatibilty Complex (MHC-II) and costimulatory molecules in their cell
surface, but they also interfere with different pathways of the immune response by means of direct cell-to-cell
interactions and soluble factor secretion. In vitro, MSCs inhibit cell proliferation of T cells, B-cells, natural killer
cells (NK) and dendritic cells (DC), producing what is known as division arrest anergy. Moreover, MSCs can
stop a variety of immune cell functions: cytokine secretion and cytotoxicity of T and NK cells; B cell maturation
and antibody secretion; DC maturation and activation; as well as antigen presentation. It is thought that MSCs
need to be activated to exert their immunomodulation skills. In this scenario, an inflammatory environment
seems to be necessary to promote their effect and some inflammation-related molecules such as tumor
necrosis factor-α and interferon-γ might be implicated. It has been observed that MSCs recruit T-regulatory
lymphocytes (Tregs) to both lymphoid organs and graft. There is great controversy concerning the
mechanisms and molecules involved in the immunosuppressive effect of MSCs. Prostaglandin E2,
transforming growth factor-β, interleukins- 6 and 10, human leukocyte antigen-G5, matrix metalloproteinases,
indoleamine-2,3-dioxygenase and nitric oxide are all candidates under investigation.

In vivo studies have shown many discrepancies regarding the immunomodulatory properties of MSCs. These
studies have been designed to test the efficacy of MSC therapy in two different immune settings: the
prevention or treatment of allograft rejection episodes, and the ability to suppress abnormal immune response
in autoimmune and inflammatory diseases. Preclinical studies have been conducted in rodents, rabbits and
baboon monkeys among others for bone marrow, skin, heart, and corneal transplantation, graft versus host
disease, hepatic and renal failure, lung injury, multiple sclerosis, rheumatoid arthritis, diabetes and lupus
diseases. Preliminary results from some of these studies have led to human clinical trials that are currently
being carried out. These include treatment of autoimmune diseases such as Crohn’s disease, ulcerative colitis,
multiple sclerosis and type 1 diabetes mellitus; prevention of allograft rejection and enhancement of the
survival of bone marrow and kidney grafts; and treatment of resistant graft versus host disease. We will try to
shed light on all these studies, and analyze why the results are so contradictory.

Abstract:Mesenchymal stem cells (MSCs) have been isolated from a variety of tissues, such as bone
marrow, skeletal muscle, dental pulp, bone, umbilical cord and adipose tissue. MSCs are used in regenerative
medicine mainly based on their capacity to differentiate into specific cell types and also as bioreactors of
soluble factors that will promote tissue regeneration from the damaged tissue cellular progenitors.

In addition to these regenerative properties, MSCs hold an immunoregulatory capacity, and elicit
immunosuppressive effects in a number of situations. Not only are they immunoprivileged cells, due to the low
expression of class II Major Histocompatibilty Complex (MHC-II) and costimulatory molecules in their cell
surface, but they also interfere with different pathways of the immune response by means of direct cell-to-cell
interactions and soluble factor secretion. In vitro, MSCs inhibit cell proliferation of T cells, B-cells, natural killer
cells (NK) and dendritic cells (DC), producing what is known as division arrest anergy. Moreover, MSCs can
stop a variety of immune cell functions: cytokine secretion and cytotoxicity of T and NK cells; B cell maturation
and antibody secretion; DC maturation and activation; as well as antigen presentation. It is thought that MSCs
need to be activated to exert their immunomodulation skills. In this scenario, an inflammatory environment
seems to be necessary to promote their effect and some inflammation-related molecules such as tumor
necrosis factor-α and interferon-γ might be implicated. It has been observed that MSCs recruit T-regulatory
lymphocytes (Tregs) to both lymphoid organs and graft. There is great controversy concerning the
mechanisms and molecules involved in the immunosuppressive effect of MSCs. Prostaglandin E2,
transforming growth factor-β, interleukins- 6 and 10, human leukocyte antigen-G5, matrix metalloproteinases,
indoleamine-2,3-dioxygenase and nitric oxide are all candidates under investigation.

In vivo studies have shown many discrepancies regarding the immunomodulatory properties of MSCs. These
studies have been designed to test the efficacy of MSC therapy in two different immune settings: the
prevention or treatment of allograft rejection episodes, and the ability to suppress abnormal immune response
in autoimmune and inflammatory diseases. Preclinical studies have been conducted in rodents, rabbits and
baboon monkeys among others for bone marrow, skin, heart, and corneal transplantation, graft versus host
disease, hepatic and renal failure, lung injury, multiple sclerosis, rheumatoid arthritis, diabetes and lupus
diseases. Preliminary results from some of these studies have led to human clinical trials that are currently
being carried out. These include treatment of autoimmune diseases such as Crohn’s disease, ulcerative colitis,
multiple sclerosis and type 1 diabetes mellitus; prevention of allograft rejection and enhancement of the
survival of bone marrow and kidney grafts; and treatment of resistant graft versus host disease. We will try to
shed light on all these studies, and analyze why the results are so contradictory.